Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases

Abstract

Until 2004, many researchers believed that protein methylation in eukaryotic cells was an irreversible reaction. However, the discovery of lysine-specific demethylase 1 in 2004 drastically changed this view and the concept of chromatin regulation. Since then, the enzymes responsible for lysine demethylation and their cellular substrates, biological significance, and selective regulation have become major research topics in epigenetics and chromatin biology. Many cell-permeable inhibitors for lysine demethylases have been developed, including both target-specific and nonspecific inhibitors. Structural understanding of how these inhibitors bind to lysine demethylases is crucial both for validation of the inhibitors as chemical probes and for the rational design of more potent, target-specific inhibitors. This review focuses on published small-molecule inhibitors targeted at the two flavin adenine dinucleotide-dependent lysine demethylases, lysine-specific demethylases 1 and 2, and how the inhibitors interact with the tertiary structures of the enzymes.

Kinetics, mechanism, and inhibition of monoamine oxidase

“…For instance, they inhibit cytochrome P450 enzymes (Hanzlik and Tullman 1982;Khan et al 2013;Salsali et al 2004), copper amine oxidases (Shepard et al 2003), prostacyclin synthase and alcohol dehydrogenase (Talele 2016;Khan et al 2013). More importantly, cyclopropylamines also show cross reactivity with the histone demethylases (Lysine-Specific Demethylase (LSD) 1 and 2) that play a vital role in regulation of gene expression (Schmidt and McCafferty 2007;Binda et al 2010;Niwa and Umehara 2017).…”

Inhibition of FAD-dependent lysine-specific demethylases by chiral polyamine analogues

“…11,[13][14][15][16][17] Since LSD1 is involved in tumorigenesis and progression of various cancers, LSD1-specic inhibitors are considered as not only chemical tools for biomedical research, but also as potential anticancer agents. 18,19 Most cell-permeable LSD1 inhibitors reported so far, including ours, 17 are based on the tranylcypromine scaffold, and are irreversible, covalently reacting inhibitors. 15,19 On the other hand, no LSD2-specic inhibitors have yet been developed, which hinders the study of the chemical biology of LSD2.…”

Drug Design Concepts for LSD1‐Selective Inhibitors

“…To date, a number of LSD1 inhibitors has been developed . LSD1 inhibitors are mainly categorized into two types, irreversible inhibitors and reversible inhibitors.…”

“…Thus, the development of LSD1 selective‐inhibitors is highly desired. Currently, several irreversible LSD1 inhibitors [e. g., ORY‐1001 ( 4 ), GSK2879552 ( 5 ), ORY‐2001, INCB‐059872, IMG‐7289 and CC‐90011] are being tested in clinical trials for cancers and neurodegenerative disorders ,…”